Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a member of the CD28-B7 immunoglobulin superfamily of immune regulatory molecules. Greenwald et al., Ann. Rev. Immunol. 23:515-548 (2005). Although initially mischaracterized as a positive regulator based on homology to its co-stimulatory counterpart CD28, CTLA-4 has now been recognized as one of the key negative regulators of adaptive immune responses in general, and T cell proliferation and effector functions in particular. Peggs et al., Curr. Opin. Immunol. 18:206-213 (2006). Unlike constitutively-expressed CD28, CTLA-4 expression is tightly regulated and short-lived on activated T cells, and exhibits significantly higher affinities for the B7 ligands it shares with CD28.
A number of clinical efforts are underway to therapeutically exploit the important biological function of this molecule. On the one hand, CTLA-4Ig fusion molecules have been created and employed as immune suppressants in vivo based on its higher affinity for B7 and the consequent inhibition of CD28-B7 mediated costimulation. Bluestone et al., Immunity 24:233-38 (2006). The hCTLA-Ig fusion protein Orencia™ (abatacept) recently received FDA approval as a first-in-class antagonist of CD28 costimulation in rheumatoid arthritis.
On the other hand, CTLA-4 blockade is being explored as a promising approach to cancer immunotherapy, employing monoclonal antibodies directed against CTLA-4 to prevent its negative regulation and thereby enhance the cellular immune response. Peggs, supra. Ongoing clinical investigations utilizing systemic administration of these antibodies have provided dramatic successes, but have also produced undesirable toxicities. In particular, adverse immune events (AIE) such as immune-mediated colitis, hypophysitis, uveitis and hepatitis have been observed, and serious AIE often correlate with antitumor responses or freedom from relapse. Attia at al., J. Clin. Oncol. 23:6043-53 (2005). Accordingly, although the current systemic approach may be clinically acceptable in a patient population having advanced disease and very limited treatment options, further improvement is clearly warranted to dissociate the positive anti-tumor effect from the negative adverse events.